Predominant diseases characterized by a lack of regeneration of cells or deregulated apoptosis are sarcopenia and cachexia. The etiology of sarcopenia is multifactorial but still poorly understood while the sequelae of this phenomenon, i.e. loss of independence and metabolic complications, represent a major public health problem. The most evident metabolic explanation for muscle decline in elderly people is an imbalance between protein synthesis and breakdown rates but other causes like disproportionately increased rate of programmed cell death (apoptosis), neurodegenerative processes, reduction in anabolic hormone productions or sensitivity such as insulin, growth and sex hormones, dysregulation of cytokine secretions, modification in the response to inflammatory events, inadequate nutritional intakes and sedentary lifestyle are involved. A multimodal approach combining nutrition, exercise, hormones, specific anabolic drugs may be treatment regimens for limiting the development of sarcopenia with aging. However, all therapy approaches have severe disadvantages, for instance hormones and anabolic drugs often have severe side effects. A consensus definition of sarcopenia is disclosed in von Haehling et al., J Cachexia Sarcopenia Muscle (2010) 1:129-133.
Sarcopenia and lack of physical activity are connected. However, physical activity alone cannot prevent sarcopenia completely. Treatment strategies of sarcopenia are unsatisfying. The most common therapies are application of hormones that interact with muscle growth such as testosterone. Unfortunately, it has been shown that treatment with testosterone may induce a variety of side effects such as cardiovascular diseases or cancer.
Sarcopenia is usually seen in elderly people, but can also be observed in young adults, like dementia. The prevalence of sarcopenia in 60-70 year old people is 5-11%, whereby in people over 80 years it is 11-50%. It is estimated that 200 million people will suffer from this syndrome over the next 30 years (Cruz-Jentoft A., Age and Ageing 2010, 39).
Not only people with age-related sarcopenia are affected, but also patients being bedridden, having tumors or people without physical activity have a marked decrease of muscle tissue. The enormous costs for the health care system for these patients together with the fast increase of the aging population and concomitantly the increase of age-related sarcopenia demands an efficient therapy for sarcopenia.
Cachexia is defined as physical wasting with loss of muscle mass and weight that is caused by disease. It is common for elderly individuals who have disease to exhibit cachexia. Additionally, muscle mass loss is characteristic of the conditions of frailty and sarcopenia. Physical frailty is a condition that results from reduced strength, reduced gait velocity, reduced physical activity, weight loss, and exhaustion. Sarcopenia and frailty could be classified as cachectic conditions because they are associated with muscle mass loss.
Apoptosis describes the so called programmed cell death, which is an active process by which cells get destructed. This destruction undergoes some characteristic morphological changes, like chromatin condensation, cell shrinkage, membrane blebbing, and formation of apoptotic bodies. It is known, that the cells in the adult body are in a perfect balance between cell division and controlled cell death. There are different events where apoptosis occurs, e.g. in the formation of fingers and toes in the human embryonic development or when cells are degenerated, nonfunctional and/or potentially dangerous to the animal. Apoptosis is characterized by a controlled sequence of events. The first sign is condensation of chromatin, DNA-fragmentation, expression of proteolytic enzymes and finally cell destruction. These biochemical and morphological changes can be measured with different methods, whereat it is very important to choose examination methods, which are able to distinguish between apoptosis and necrosis, because some of them just detect cell death in general.
Available evidence suggests that targeting myonuclear apoptosis provides novel and effective therapeutic tools to combat sarcopenia (Marzetti E. et al. (2012) Gerontology 58/2:99-106). Since loss of muscle cell mass is a serious problem for elderly people it would be of great importance to provide a therapy that regains muscle strength for these patients. Muscle cell loss is also known as sarcopenia. There is currently no satisfying therapy for this disease and induction of muscle cell growth might lead to a new and innovative therapy for sarcopenia. Muscle cell loss results from an imbalance between cell division and controlled cell death (apoptosis).
It is a goal to find suitable pharmaceutical agents and methods to stimulate cell growth and/or reduce apoptosis for the treatment of various wasting diseases.